title: A selective inhibitor of drp1, mdivi-1, increases retinal ganglion cell survival in acute ischemic mouse retina.
abstract: OBJECTIVE
  To determine whether acute intraocular pressure (IOP) elevation alters dynamin-related protein 1 (Drp1) as well as whether a selective inhibitor of Drp1, mdivi-1, can block apoptotic cell death and subsequently increase retinal ganglion cell (RGC) survival in ischemic mouse retina.
  
  
  METHODS
  C57BL/6 mice received injections of mdivi-1 (50 mg/kg) or vehicle, and then transient retinal ischemia was induced by acute IOP elevation. RGC survival was measured after FluoroGold labeling. Drp1 and glial fibrillary acidic protein (GFAP) protein expression and distribution were assessed at 12 hours after ischemia-reperfusion by Western blot and immunohistochemistry. Apoptotic cell death was assessed by TUNEL staining.
  
  
  RESULTS
  Drp1 and GFAP protein expression was significantly increased in the early neurodegenerative events (within 12 hours) of ischemic mouse retina. Mdivi-1 treatment blocked apoptotic cell death in ischemic retina, and significantly increased RGC survival at 2 weeks after ischemia. In the normal mouse retina, Drp1 is expressed in the ganglion cell layer (GCL) as well as the inner plexiform layer, the inner nuclear layer (INL), and the outer plexiform layer (OPL). In the GCL, Drp1 immunoreactivity was strong in RGCs. While Drp1 protein expression was increased in the GCL of vehicle-treated ischemic retina at 12 hours. Mdivi-1 treatment did not change this increase of Drp1 protein expression but significantly decreased GFAP protein expression.
  
  
  CONCLUSIONS
  These findings suggest that altered Drp1 activity after acute IOP elevation may be an important component of a biochemical cascade leading to RGC death in ischemic retina.
authors.affiliation: Sophie and Arthur Brody Optic Nerve Laboratory, Hamilton Glaucoma Center, University of California San Diego, La Jolla, California 92037, USA.
authors.forename: Sang Woo
authors.initials: SW
authors.lastname: Park
authors.forename: Keun-Young
authors.initials: KY
authors.lastname: Kim
authors.forename: James D
authors.initials: JD
authors.lastname: Lindsey
authors.forename: Yi
authors.initials: Y
authors.lastname: Dai
authors.forename: Hwan
authors.initials: H
authors.lastname: Heo
authors.forename: Duy H
authors.initials: DH
authors.lastname: Nguyen
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.forename: Robert N
authors.initials: RN
authors.lastname: Weinreb
authors.forename: Won-Kyu
authors.initials: WK
authors.lastname: Ju
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007429:Intraocular Pressure; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009798:Ocular Hypertension / Q000150:complications; D052999:Quinazolinones / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D012164:Retinal Diseases / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology*; D012171:Retinal Vessels
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D052999:Quinazolinones; C528900:glial fibrillary astrocytic protein, mouse; D020558:GTP Phosphohydrolases; C486391:Dnm1l protein, mouse; D034281:Dynamins